Functional deficiency of the FENl gene is suggested to cause genomic instability and cancer predisposition.We have identified a group of FEN1 mutations in human cancer specimens.Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1).To demonstrate the etiological significance of these somatic mutations,we have in-bred a mouse line harboring the E160D mutation representing those identified in human cancers.Selective elimination of nuclease activities leads to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells.The mutant mice were predisposed to autoimmunity,chronic inflammation,and cancers.